Bruton’s Tyrosine Kinase Mediates NF-κB Activation and B Cell Survival by B Cell-Activating Factor Receptor of the TNF-R Family

Abstract

Loss of Bruton’s tyrosine kinase (Btk) function results in mouse Xid disease characterized by a reduction in mature B cells and impaired humoral immune responses. These defects have been mainly attributed to impaired BCR signaling including reduced activation of the classical NF-κB pathway. In this study we show that Btk also couples the receptor for B cell-activating factor (BAFF) of the TNF family (BAFF-R) to the NF-κB pathway. Loss of Btk results in defective BAFF-mediated activation of both classical and alternative NF-κB pathways. Btk appears to regulate directly the classical pathway in response to BAFF such that Btk-deficient B cells exhibit reduced kinase activity of IκB kinase γ-containing complexes and defective IκBα degradation. In addition, Btk-deficient B cells produce reduced levels of NF-κB2 (p100) basally and in response to stimulation via the BCR or BAFF-R, resulting in impaired activation of the alternative NF-κB pathway by BAFF. These results suggest that Btk regulates B cell survival by directly regulating the classical NF-κB pathway under both BCR and BAFF-R, as well as by inducing the expression of the components of alternative pathway for sustained NF-κB activation in response BAFF. Thus, impaired BCR- and BAFF-induced signaling to NF-κB may contribute to the observed defects in B cell survival and humoral immune responses in Btk-deficient mice.

A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenström macroglobulinemia

“…Although IkBa is a downstream component of the IRAK signaling cascade, other pathways can also trigger its activation including BTK. 29,30 BTK is constitutively activated in WM cells and its inhibition blocks IkBa activity in WM cells as shown in these studies. We therefore sought to determine whether MYD88 L265P was responsible for the BTK activation in WM cells.…”

NIK overexpression amplifies, whereas ablation of its TRAF3-binding domain replaces BAFF:BAFF-R-mediated survival signals in B cells

“…These results support the notion that BAFF:BAFF-R interactions mainly stimulate the alternative branch via IKK1 and NIK, which is further underlined by our finding that even strong overproduction of NIK⌬T3 leads to only weak stimulation of events associated with canonical NF-B activity. However, although most of the experimental evidence points to a minor role of BAFF in the induction of canonical NF-B in murine B cells, there is evidence that BAFF treatment can induce significant canonical NF-B activity also in the mouse (27,28). Therefore, the exact mechanism of BAFF-induced canonical NF-B and its importance in the context of human and murine B cell survival remain to be determined.…”

Canonical NF-κB signaling is uniquely required for the long-term persistence of functional mature B cells

“…In this scenario, the occasional engagement of the BCR on resting mature B cells by antigens in the environment, with a resulting activation of the canonical NF-κB pathway, might enhance the competitive fitness of the cells in their ability to access survival niches (22). The activation of canonical NF-κB signaling downstream of the BCR and/or BAFFR could be mediated by Bruton's tyrosine kinase (Btk) (5,25). Indeed, similar to the behavior of follicular B cells in the absence of canonical NF-κB signals, ectopic expression of Bcl2 rescues the generation of follicular B cells in x-linked immunodeficiency (xid) mice, which bear a mutation in Btk, and CD23 + transitional and follicular xid B cells are outcompeted by WT B cells (26,27).…”